Method and apparatus for generating nitric oxide for medical use

ABSTRACT

A method and system for generating and delivering nitric oxide directly to a patient. A reaction chamber is provided that is located at or in close proximity to the patient and reactants within the reaction chamber react together to produce a predetermined amount of nitric oxide. The reaction is controlled by metering at least one of the reactants into the reaction chamber to generate a predetermined quantity of nitric oxide as required by the patient. The reactants can include a nitrite salt, such as sodium nitrite, and a reductant such as ascorbic acid, maleic acid or a mixture thereof. By generating and delivering the nitric oxide directly to the patient in close proximity thereto, the formation of NO2 is minimized. One or both of the reactants may be in liquid form.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Non-Provisional patentapplication Ser. No. 14/307,664, filed Jun. 18, 2014, which is itself acontinuation of U.S. Non-Provisional patent application Ser. No.11/355,670, filed Feb. 16, 2006, which issued as U.S. Pat. No. 8,790,715on Jul. 29, 2014, the entire disclosures of which are incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to a method and system for generating andadministering nitric oxide (NO) to a patient, and, more particularly, toa method and system that generates the NO proximate to and for immediatedelivery to the patient.

BACKGROUND OF THE INVENTION

The administration of nitric oxide (NO) gas via inhalation for treatingpatients with pulmonary hypertension is described in Zapol andFrostell's U.S. Pat. No. 5,485,827 “Methods and Devices for TreatingPulmonary Vasoconstriction and Asthma”.

At the present, nitric oxide gas is commonly used for the treatment ofpersistent pulmonary hypertension in the newborn and is indicated forthe treatment of term and near-term (>34 weeks) neonates with hypoxicrespiratory failure (HRF) associated with clinical or echocardiographicevidence of pulmonary hypertension. In babies with HRF, blood vessels inthe lungs constrict, making it difficult for the heart to pump bloodthrough the lungs for oxygenation. Nitric oxide is a pulmonaryvasodilator, which relaxes the blood vessels of the lungs in newbornswhose heart and lungs could not otherwise carry enough oxygenated bloodto the body tissues.

There are also other clinical applications in which NO is used to treatsurface infections on the skin of a patient as described in U.S. Pat.No. 6,432,077.

U.S. Pat. No. 5,670,127 “Process for the Manufacture of Nitric Oxide”(Lien-Lung Sheu) describes a method for producing nitric oxide, NO, formedical use by reacting aqueous nitric acid with gaseous sulfur dioxidein a gas-liquid contact reactor to produce 100% NO gas. It is importantto note that all of the reactants used in this method are hazardous tohandle and, accordingly, the process has to be strictly controlled. TheNO produced by this method, which is close to 100%, is blended with aninert diluent, preferably nitrogen, to produce a pressurized gas sourcein a safe and useable concentration, currently in the range of 100 to800 ppm of NO. Because this method uses cylinder concentrations in theparts per million (ppm) level it requires the use of large pressurizedcylinders (approximately 175 mm diameter and 910 mm high with a wettedvolume of 16 Land a weight of 18 Kg), which are bulky, heavy, andprovide logistical problems and safety requirements associated with thehandling of large pressurized gas cylinders. The cylinders arepressurized to 150 Bar and hold approximately 2000 L of useable gas.However, at a concentration of 800 ppm NO gas, the total drugs quantityis 0.066 moles which weighs only 2 gms. Hence, it can be seen that thedrug packaging represents 9,000 times the weight of the drug containedtherein.

Nitric oxide readily combines with oxygen (O₂) to form nitrogen dioxide(NO₂), a known toxic gas, so it is very important that the gas cylinderdoes not become contaminated with oxygen. It is for this reason that thediluent gas used in the cylinders is one that is inert to, i.e. will notoxidize, nitric oxide. While a number of such inert gases are known, itis preferred to utilize nitrogen, N2, primarily on the basis of cost.

The delivery apparatus for dispensing gaseous NO has to deliver the NOsource gas into the patient's respirable gas to give a concentration inthe range of 1-80 ppm to the patient's lung in a precise andcontrollable manner. It also has to deliver it in a manner thatminimizes the formation of NO₂. The parameters that are relevant to theformation of NO₂ are the square of the NO concentration, the O₂concentration and the time for the reaction between them to take place.The O₂ concentration is not normally controllable by the NO deliverydevice and the source gas is at a fixed concentration, therefore, thetime for the reaction to take place is the only variable.

Apparatus for the delivery of nitric oxide (NO) from a gas cylinder hasto not only precisely deliver the correct dose of NO to the patient, butalso to minimize the time from delivery to when the patient breathes inthe gas to prevent the formation of NO₂ at unsafe levels. An example ofa bedside NO delivery device that achieves these two functions isdescribed in U.S. Pat. No. 5,558,083 which shows how a constantconcentration of NO can be delivered to a patient who is on a gasdelivery system such as a ventilator. Smaller ambulatory NO deliverydevices are described in U.S. Pat. Nos. 6,089,229, 6,109,260, 6,125,846,and 6,164,276, which describe how dosing can be provided in a pulse modewhile keeping NO₂ levels at an acceptably low level. While these pulsedevices allow a compact and low weight delivery device to be made, theystill require the bulk and weight of the NO cylinder for NO to bedelivered.

Because of the challenges surrounding the current method of producing,distributing and safely administrating nitric oxide from pressurizedcylinders to a patient, there have been a number of alternate solutionsproposed to generate NO locally and to immediately deliver it to thepatient. Some of those alternate solutions include using an electric arcdischarge to produce NO from air prior to delivering it to a patient(U.S. Pat. No. 5,396,882): producing NO for inhalation by establishing acoulometric reduction of copper ions in a solution of nitric acid alongwith purging the chamber with an inert gas (U.S. Pat. No. 5,827,420);using a corona discharge to generate NO in a chamber that containsoxygen and nitrogen (EP 0719159); using a plasma chemical reactionmethod while heating the reaction chamber to 400-800° C. to obtain highefficiency of NO production (U.S. Pat. No. 6,296,827); and using heat tobreakdown an organic nitrogen-containing compound, such as ammonia, toform NO (U.S. Pat. No. 6,758,214).

Each of the proposed solutions, however, has certain drawbacks in thegeneration of NO for direct delivery to the patient rather than havingto handle the bulk and weight of pressurized gas cylinders and all ofthe proposed solutions fail to meet at least one of the requirements fora successful portable and safe NO generation system for the immediatedelivery of NO to a patient. These requirements can include (1) compactsize for easy handling (<100 mm×150 mm×50 mm); (2) low weight for easyportability (<2 Kgs), (3) no toxic compounds or byproducts that wouldraise safety concerns, (3) any reactants used should be readilyavailable and not have any special storage or handling requirements, (4)low electrical power consumption so that battery operation is possibleif necessary, (5) accurate, controllable generation of NO in just theamount needed for the patient and (6) fast generation so NO can be madeand delivered to a patient without allowing NO₂ to form.

Accordingly, it would be advantageous to have a method and device forthe local generation of NO for immediate delivery to the patient andwhich overcomes the drawbacks and difficulties of the prior attemptedsolutions and which also possesses all of the desirable characteristicsof such a system.

SUMMARY OF THE INVENTION

This invention describes methods and devices for the local generation ofNO for immediate delivery to a patient that is compact, low weight,requires no toxic reactant compounds, uses low electrical power andprovides fast and controllable NO generation. A general aspect of theinvention is a method for producing nitric oxide (NO) for the immediatedelivery to a mammal, i.e. human or animal by bringing togethercontrollable quantities of a nitrite salt, preferably sodium nitrite,and a reductant, preferably at least one of ascorbic acid and maleicacid, in the presence of water in the desired quantities to produce theamount of NO required by the mammal and for the NO to then beimmediately delivered to the mammal. Preferably, NO produced inaccordance with the present invention is delivered for inhalation by themammal. By generating the NO within the apparatus immediately prior todelivering it to the mammal, the time for NO₂ formation is kept to aminimum. These and other features and advantages of the presentinvention will become more readily apparent during the followingdetailed description taken in conjunction with the drawings herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a device that can be used for carrying outthe present invention,

FIG. 2 is a schematic view of an alternative device that can be used forcarrying out the present invention,

FIG. 3 is a schematic view of another alternative device that can beused for carrying out the present invention,

FIG. 4 is a schematic view of a still further alternative device thatcan be used for carrying out the present invention,

FIG. 5 is a schematic view of yet another alternative device that can beused for carrying out the present invention,

FIG. 6 is a perspective view of a membrane separation tube usable withthe present invention,

FIG. 7 is a schematic view of a system for using the present inventionwith a spontaneously breathing patient,

FIG. 8 is a schematic view of a system for using the present inventionwith a mechanically ventilated patient,

FIG. 9 is a schematic view of a test set up for carrying out testing ofthe present invention,

FIG. 10 is an illustration of the test results for NO concentrations forExample 1 using the present invention,

FIG. 11 is an illustration of the test results for NO concentrations foranother Example of a use of the invention, and

FIG. 12 is a schematic view of a further system for use of the presentinvention with a NO concentration setting capability.

DETAILED DESCRIPTION OF THE INVENTION

The present invention uses a nitrite and a reductant in the presence ofwater to generate NO in gaseous form. In an exemplary embodiment, thenitrite source is sodium nitrite and the reductant is at least one ofascorbic acid and maleic acid, preferably ascorbic acid. The use ofthese exemplary reactants assures that the materials used to produce theNO are both non-toxic; that is, ascorbic acid is Vitamin C and sodiumnitrite is used in curing meats, such as ham, and the like. Therefore,the reactant compounds can be used in proximity to the patient withoutthe danger of toxic materials passing downstream to ultimately reach thepatient. As used herein, the term “patient” refers to a human or ananimal, preferably the former. In addition, all the reactant compoundsare soluble in water, therefore, solutions containing equimolarquantities thereof can readily be prepared The reaction that produces NOwhen generated by sodium nitrite and ascorbic acid in accordance withthe present invention can be illustrated by Equation 12NaNO₂+2C₆H₈O₆=>2NO+2NaC₆H₇O₆+H₂O+½O₂  Equation 1

The reactant compounds used to generate NO according to Equation 1 arewidely used in the food industry and are non-toxic in the quantitiescontemplated herein as described above.

One embodiment of the invention is an apparatus that uses an aqueoussolution of sodium nitrite that is deposited as liquid droplets in acontrolled amount onto an molar excess of ascorbic acid (in solid formor as an aqueous solution). Preferably, very fine droplets are utilized,thus enabling the reaction to proceed quickly and the NO thus-formedavailable for inhalation or application.

The amount of NO provided from the reaction is governed by controlling aprecise amount of liquid to be brought into contact with the otherreactant or reactants. The liquid being dispensed into the reactionchamber is preferably aqueous solutions of the nitrite and/or thereductant. If both the nitrite and the reductant are in a solid state ona substrate, the liquid dispensed to initiate and control the reactionwill be water.

The aqueous solutions utilized to generate NO in accordance with thepresent invention may contain different molar strengths of sodiumnitrite with the size of the liquid reservoir required varying inverselywith the molar concentration. For instance, utilizing a 6 molar aqueoussolution of sodium nitrite, the amount of solution that would producethe same number of moles of NO as are contained in the 16 L cylinderdescribed above would be just 12 mL and weigh only 12.4 grams. Given aplastic package/housing for the solution (similar to an inkjet printercartridge), the size would be approximately 30 mm×45 mm×45 mm and weigharound 20 gms, or a total weight of 33 grams. As can be seen comparedwith the gas cylinder for NO, this gives significant improvement withregard to the drug package size and weight.

To determine the amount of liquid to be dispensed, it is necessary toquantify the amount of NO required by a patient. The typical range of NOconcentration being inhaled by a patient to reduce pulmonaryhypertension is 5 to 80 ppm of NO. A typical alveolar volume per patientbreath is around 300 to 400 mL at rest. The amount of NO required perbreath can therefore be calculated from equation 2.N=P·V/(Ru·T)  (2)

Where:

-   -   N is the number of moles of the gas (mole)    -   P is the absolute pressure of the gas (joule/m3)    -   V is the volume of the particular gas (m3)    -   Ru is the universal gas constant, 8.315 (joule/gmole. ° K)    -   T is the absolute temperature (° K)

Assuming atmospheric pressure (101,315 joule/m3) and 20° C. (293° K) asthe temperature and expressing the volume in mL (×10⁻⁶ m3), equation (2)reduces to:N=4.16×10⁻⁵ ·V (moles)  (3)

Equation (3) can be used to calculate the number of moles of NO gas tobe delivered to a patient's alveolar volume for a specifiedconcentration by using equation (4).N _(NO) ═C _(NO)·10⁻⁶·4.16×10⁻⁵ ·Va  (4)

Where;

-   -   C_(NO) is the concentration of NO (ppm)    -   Va is the alveolar volume (mL)

For example if the NO concentration required is 5 ppm and the alveolarvolume is 300 mL, the amount of NO in moles to be delivered to thepatients alveoli per breath would be;N _(NO)=5×10⁻⁶·4.16×10⁻⁵·300=250×10⁻⁹ moles or 62 nmoles.

The molecular weight of sodium nitrite is 69. Hence, a one molarsolution contains 69 grams of sodium nitrite per liter. Assuming thereaction described above is 100% efficient and all of the NO producedfrom the nitrite is in gaseous form, one nmole of NO gas will beproduced for every nL of a one molar solution of sodium nitrite.

The quantity of liquid needed can be reduced by increasing the strengthof the solution. For example, if a 2 molar solution were used, then theamount of liquid needed would be reduced by 50 percent. The amount ofliquid can be produced as one droplet of exactly the right size ormultiple droplets of a smaller size which add up to the amount needed.

Therefore, it is apparent that it is possible in accordance with thepresent invention to accurately control the formation of the NO in orderto treat the individual patient with specific regard to the desiredconcentration of the NO to be delivered and the alveolar volume of thepatient.

The bringing together of the two reacting compounds can be achieved in anumber of ways. Preferably, a reactant in aqueous solution can bedelivered by a suitable liquid dispensing means to the other reactant,which may be in liquid or solid form. In another embodiment, both thenitrite salt and the reductant are in solid form on a substrate andcontrolled amounts of water are dispensed onto the substrate to allow acontrolled amount of the reactants to react thereby generating acontrolled amount of NO.

Turning to FIG. 1, there is shown a schematic view of a system that canbe used where one of the reactants is utilized as an aqueous solutionand the other is a solid. In the exemplary embodiment of FIG. 1, therecan be seen a liquid reactant source 10 that can be an aqueous solutionof a nitrite salt. The liquid nitrite from the source 10 is withdrawn orpumped out by a liquid dispensing means in the form of a controllablemicro pump 12 so that the liquid nitrite enters a housing 14 enclosing areaction chamber 16. The housing 14 also has formed therein an inlet 18for admitting room air or other carrier gas and an outlet 20 fordischarging the NO-laden carrier gas from the reaction chamber 16 todeliver that gas to a patient. The liquid dispensing means or micro pump12 can be constructed through a number of different technologies thatcould be used to dispense nanoliter amounts of liquid.

One possible technology can involve individual micro pump valves whichopen for a short period of time and allow liquid from a pressurizereservoir to be delivered through a small orifice (0.1 to 0.25 mmdiameter) while in the open phase. Another technology for the micro pump12 can be through the use of inkjet style printer heads (piezoelectricor thermal) to deliver the fine droplets required. Typical inkjetprinter heads have droplet sizes of 10 to 100 picoliters (100×10⁻¹² L)which is substantially smaller than would be required in the practice ofthe present invention. However, such ink jet printer heads can have upto 100 orifices per printhead and can deliver droplets at a rate of upto 12 MHz. Accordingly, by delivering multiple droplets from multipleorifices, the total amount required can be delivered very quickly. Forinstance, 100 orifices delivering simultaneously 6 droplets/orificewould be needed to deliver the 62 nL in the example above.

A disk 22 of substrate material, such as polyethylene, has a thin layerof the other reactant, i.e. the reductant, coated on a reaction surface,that is, the upper surface 24 thereof such that the liquid nitritedroplets hit the coating of the reductant on the upper surface 24 of thedisc 22 to allow the reaction to take place as has been previouslyexplained, thereby forming NO gas that then passes through the outlet 20to enter the airway of the patient. In order to continue the process,the disc 22 can be rotated to advance to a new position after each localreaction from a droplet, and the position of the micro pump 12 can movealong a linear path from the outside of the disc 22 to the inside tocreate a spiral thereby using all of the available reactant that ispresent on the upper surface 24 of the disc 22. As can be seen, thereaction is controlled by the rate the reactant liquid is caused toenter into the reaction chamber 16 and contact the solid reactant.

In FIG. 2 there is shown a schematic view of an alternate embodimentwhere a liquid reactant is contacted with a solid reactant. In theembodiment shown in FIG. 2, the basic components are the same and havebeen give the same identification numbers, however, in this embodiment,the reaction takes place on a tape 26 that is movable. As such, as eachdroplet falls from the micro pump 12, it hits the thin layer of theother reactant that is coated to the upper surface 28 of the tape 26where the reaction takes place. After each droplet reacts, the tape 26can be moved to provide another area of the solid reactant coating toreceive a subsequent droplet. If the tape 26 is wide, the position ofthe micro pump 12 can move along a lateral linear path that is at aright angle to the direction of the movement of the tape 26, to use allthe available reactant that is present on the upper surface 28 of thetape 26.

Turning now to FIG. 3, there is shown a schematic view of a systemwherein both of the reactants are present in liquid form with, again,only a single liquid dispensing means being utilized.

Thus, in FIG. 3, there can be seen a liquid reactant source 10 that canbe liquid nitrite compound, such as an aqueous solution of sodiumnitrite. Again, the liquid nitrite from the source 10 is withdrawn orpumped out by a liquid dispensing means in the form of a controllablemicro pump 12, so that the liquid nitrite enters a housing 14 enclosingthe reaction chamber 16. In this embodiment, however, the otherreactant, i.e. the reductant, is in liquid form and is located in areservoir 30 formed in the housing 14.

The droplet of the nitrite thereupon falls from the micro pump 12 downinto the liquid reductant, so as to react therewith and form the NO gasthat is passed through the outlet 20 to the airway of the patient. Sincethe supply of the liquid reductant is by means of a reservoir, it willbe appreciated that there is no need to move the location of the micropump 12. Again, the reaction that takes place between the reactants, andtherefore the production of NO, is controlled by controlling the rate atwhich the droplets of nitrite are introduced into the reaction chamber16 to react with the liquid acid reductant since the reaction will takeplace only so long as there is nitrite salt present to react.

Turning next to FIG. 4, there is an exemplary embodiment of analternative embodiment to the FIG. 3 embodiment and where there is aroller 32 having an outer surface that is partially disposed below thesurface of the liquid reductant such that, as the roller 32 rotates,fresh liquid reductant is continually brought out of the reservoir 30 soas to be positioned to receive a droplet of the liquids nitrite from themicro pump 12. As such, as a droplet of the liquid nitrite hits theupper area of the outer surface of the roller 32 to react with theliquid reductant located thereon, the roller 32 can be rotated to bringa fresh supply of the liquid reductant in position to receive the nextdroplet. To speed up the reaction, the outer surface of the roller 32can be roughened to increase the local surface area.

Turning to FIG. 5, there is shown a schematic view of a system whereboth of the reactants are in aqueous solution and there is a pair ofliquid dispensing means. As can be seen, therefore, there is a nitritesource 34 and a reductant source 36, both of which have their respectiveliquids removed therefrom by means of micro pumps 38 and 40. Therespective droplets are then dispensed onto a reaction surface 42 withinthe reaction chamber 16. There is a movement system by which thereaction surface 42 is moved to assure that the two droplets aredeposited at the same location on the reaction surface 42 so that theindividual droplets of reactants can react with each other. The movementsystem can move either the micro pumps 38 and 40 or the reaction surface42, or both, to make sure there is a proper alignment of the respectivedroplets to provide the reaction for producing NO.

As examples of such movement system, the reaction surface 42 can be arotating disc, a rotating cylinder or a tape advancement mechanism, eachof which are described with respect to FIGS. 2-4, and which can be usedto align or register the location of the second deposited droplet withthe first deposited droplet. In addition, the surface of the indexsubstrate can be heated to increase the reaction rate and to cause anyresidual water to be evaporated.

In any of the foregoing devices or systems, after the NO has beengenerated, the remaining reaction side product, e.g. sodium ascorbate,has to be removed from the liquid dispensing means so as to notinterfere with following reactions. Some of the solutions describedabove have inherent means in the design to do this; for example, in theFIG. 2 embodiment, as the tape 26 is advanced to its next indexposition, it automatically removes the side product compound from theliquid dispensing means and stores it on the tape 26. Similarly, as theroller 32 of the FIG. 4 embodiment rotates to bring a new supply of theliquid reactant to the upper area, that movement also removes the sideproduct compound from the reaction surface.

However in the embodiment of FIG. 5, where both of the liquid reactantsare dispensed in a controlled manner, some way of removing the sideproducts must be added. This could be a rotating cylinder that is heatedto dry the side product into a solid form where it can be scraped offinto a holding chamber below the cylinder. This holding chamber can alsohave neutralizing compounds, such as activated charcoal, to stop anyfurther reaction and to keep any cross-over from the holding chambergetting back into the reaction chamber. Another way of achieving this isto have the holding chamber at a lower pressure by pumping gas out of itand passing it through a scrubber before exhausting to atmosphere.

As stated, there can be a problem with the build up of NO₂ levels sincethat compound is toxic and therefore must be prevented from beinggenerated and administered with the NO to a patient. To that end, anumber of solutions can be employed. One such solution is to constructthe reaction chamber to be extremely small so as to reduce the washouttime and be designed with no areas that can allow stagnant gas toaccumulate and cause NO₂ to form.

Another solution is to provide the gas flow through the reaction chamberto be low in oxygen in order to reduce the NO₂ reaction rate. This canbe achieved with membrane separation technology (FIG. 6) whichpreferentially allows oxygen and water vapor to pass out of the gasstream prior to the reaction chamber. As can be seen in FIG. 6,therefore, there is a membrane separation tube 44 through which the gaspasses to be fed into the NO generating device of the present invention.Thus, as the air is moved from the inlet 46 to the outlet 48 of membraneseparation tube 44, the water vapor and oxygen, being “fast gases”,quickly permeate through the wall of the membrane separation tube 44 andallow the nitrogen to pass through the bore of the membrane to besupplied for the NO reaction of the present invention.

As a further solution, the NO₂ can be removed downstream of the chamberwith the addition of an NO₂ scrubber. Materials that can be used toremove NO₂ are sulfurous polymer (see EU 0763500A2) or soda lime.

There are a number of systems by which the present invention canadminister the NO generated to the patient. The simplest means is forthe patient to breath in through the reaction chamber so the NOgenerated is taken directly into the patients lung like an inhaler. Thepatient would simply press a button to generate the NO and then inhalethe gas mixture directly from the reaction chamber.

Rather than have the patient press a button, the device could havesensor means to detect when the patient took a breath and that wouldsignal the device to generate the NO. This detection of the patient'sinspiration could be either by pressure drop or flow indication.

Instead of a simple inhaler with the reaction chamber proximal to thepatient, there is shown, in FIG. 7, a gas delivery system for aspontaneously breathing patient that has a pump 50 that draws in roomair through a filter 52 and pumps that air through the reaction chamber54. There may also be a membrane separation tube 56 located upstream ofthe reaction chamber 54 to remove some oxygen in the manner and for thepurpose as explained with respect to the membrane separation tube 44 ofFIG. 6. It should be noted that while the pump 50 is shown locatedupstream of the reaction chamber 54, it could alternatively be locateddownstream of the reaction chamber 54 and draw the air through thereaction chamber 54.

A conduit 58 delivers the NO-containing gas from the reaction chamber 54to the patient 60 where it can be administered to the patient 60 bymeans of a patient device such as a nasal cannula 62. A nasal cannula isdesigned to provide supplemental air flow to the patient and therefore,does not form a seal with the patient's airway, so additional room airis taken in as the patient breathes. The conduit 58 could also contain abreath trigger sensor 64 to act as a breath detector to determine whenthe patient was breathing in and, therefore, when to generate the NO.The pump 50 could operate either continuously or only when NO was beinggenerated and hence work in a pulse mode to deliver gas flow through thereaction chamber 54 where the stream of gas picks up the NO and carriesit through the nasal cannula 62 and thence to the patient 60. As such,there may be a pump control 66 that controls the operation of the pump50. In addition, there is a liquid dispense control 68 that controls thereaction occurring within the reaction chamber 54 as has been previouslyexplained so that the amount of NO generated is controlled to providethe desired amount of NO to the patient 60. As also can be seen, thereis a NO sensor 70 in the conduit 58 to determine the concentration of NOleaving the reaction chamber 54.

Turning next to FIG. 8, there is a schematic view of a NO deliverysystem for use when the patient is being mechanically ventilated. As canbe seen in FIG. 8, there is, again, a pump 50 that draws in room airthrough a filter 52 and pumps that air through the reaction chamber 54with an optional membrane separation tube 56 located upstream of thereaction chamber 54. Conduit 58 delivers the NO containing gas from thereaction chamber 54 where it can be administered to the patient 60. Thisconduit 58 could also contain a breath trigger sensor 64 that senses thebreathing of a patient and a pump control 66 that can be utilized asdescribed with respect to FIG. 7. There is also a liquid dispensecontrol 68 that controls the reaction occurring within the reactionchamber 54 as has been previously explained so that the amount of NOgenerated is controlled to provide the desired concentration of NO tothe patient 60. In this embodiment, however, instead of a nasal cannula,the patient device can be a endrotracheal tube or face mask 72 thatinterjects the NO-containing gas along with the gas administered byventilator 74 through the inspiratory limb 76. The expired gases fromthe patient 60 are carried from the patient 60 through the expiratorylimb 78 back to the ventilator 74. As before, a NO sensor 70 is presentto determine the concentration of NO in the stream of gas delivered tothe patient 60. As will be appreciated, other gas delivery systems canbe used in place of a ventilator, such as a breathing bag filled withgas from a flowmeter, or a constant positive airway pressure (CPAP)where the gas flow is from a blower.

Examples of NO Generation Chamber Designs

The following examples describe different configurations of reactionchamber design which use different sources of reaction compounds (bothsolid and liquid) to generate NO. The test configuration in each casewas as described in FIG. 9 and which includes a reaction chamber 80where the reaction takes place in generating the NO. A pump 82continuously pulls in room air via an inlet 84 so as to pass through thereaction chamber 82 where the reaction takes place in the generation ofNO. A flow sensor 86 is located downstream of the reaction chamber 80that measures the total gas flow and a chemiluminescent analyzer 88carries out the analysis of the NO in the gas passing from the outlet90. The chemiluminescent analyzer 88 has a response time of 60 msec, soit is fast enough to give a real time measurement although there is a 2second lag in processing time before the measurement is available to achart recorder.

In each case the liquid dispensing means was a small pressurized (5 psi)liquid reservoir that fed a VHS micro dispensing valve (The Lee Company)using a spike voltage control circuit. The average amount of liquiddispensed was determined by gravimetric measurement over 45 minutes whenpulsing once per second.

Example 1

The first example was carried out using the apparatus of FIG. 3. Aqueoussodium nitrite (1 molar solution) was dispensed directly into a chamberwith a reservoir of liquid reductant. The reductant was 1 molar solutionof ascorbic acid with 1 molar maleic acid added. The flow through thereaction chamber (Qc) was 0.5 L/min of air and the micro pump delivered48 nL per pulse every 10 second.

Results

Average concentration of NO from the reaction chamber was approximately123 ppm as shown in FIG. 10.

The amount of NO being generated can be calculated using Equation 4where Va is the flow per second in mL given by;Va=Qc·1000/60=0.5·1000/60=8.3 mL/sec.N _(NO) =C _(NO)·10⁻⁶·4.16×10⁻⁵ ·VaN _(NO)=123·4.16·8.3/100=42.5 nmoles  Equation 4

The speed of the reaction wasn't that quick with the NO output notshowing distinct pulses but blending into a continuous output. Duringthe test, it was noticeable that the reaction was taking place somedistance below the surface of the reductant with bubbles of gas beingformed and taking some time to reach the surface. This was likelycausing a time lag in the output as the NO gas slowly bubbled out of thereductant solution.

Example 2

This next example was carried out with the use of the apparatus of FIG.4 having a chamber design where the rotary cylinder was used to bring alayer of reductant to the top of the chamber where the aqueous sodiumnitrite (1 molar solution) was dispensed onto it. This design was toreduce the delay associated with bubbles of NO forming below the surfaceof the reductant as seen in Example 1. The flow through the chamber was0.5 L/min of air and in this case the micro pump was delivering 42 nLper pulse. After each pulse, the rotary reaction surface was rotated tobring fresh reductant to the dispensing means. The rotary reactionsurface was roughed up with 400 grip sand paper to provide betterreductant retention. The reaction chamber size was also reduced in thisdesign to again speed up the response time of the NO output.

Results

As can be seen on the chart of FIG. 11, the response time of thereaction was a lot quicker with distinct pulses of NO corresponding toeach droplet of sodium nitrite solution being delivered. The totalreaction time for each pulse was less than 1 second. The peak NOconcentration was approximately 300 ppm, with an average concentrationover a 1 second period of around 117 ppm. This corresponds to an outputof about 40 nmoles of NO, but as can be seen, in a substantially reducedreaction time.

Example 3

In this example, both the nitrite and the reductant were dispensed withmicro dispensing valves that were configured to deposit the liquiddroplets at the same location at the bottom of the reaction chamber. Theapparatus was as described in FIG. 5. In this example, the sodiumnitrite was a 2 molar solution and the reductant was 1.5 molar solutionof ascorbic acid with 0.5 molar maleic acid. The micro pump delivered 42nL per pulse of sodium nitrate and the second pump delivered 54 nL perpulse of reductant both were pulsed simultaneously every second. The gasflow through the reaction chamber was 0.360 L/min of air.

Results

When the system first started up, the output was peaky as in example 2but as the liquid built up on the reaction chamber floor the outputbecame more like example 1 with the output having a longer reaction timeand an average output of NO being delivered. In the slow steady statecondition the average output was 385 ppm NO.

Based on a gas flow of 0.36 L/min this represents an NO output of 96nmoles/pulse.

Example 4

In this example, earned out using the apparatus of FIG. 1, liquid sodiumnitrite (6 molar solution) was dispensed onto a solid reductant that hadbeen formed by allowing a solution that was 1 molar in ascorbic acid and1 molar in maleic acid to evaporate onto a polyethylene disc therebyforming a crystallized thin film of reductant.

The gas flow through the chamber was 5 L/min of air.

The micro pump delivered 43 nL per pulse of the 6 molar sodium nitrate.

Results

The NO output from the reaction chamber resulted in a peak concentrationof 216 ppm NO spike which lasted about 1 second and corresponded to anaverage concentration of 73 ppm over the 1 second period. At a gas flow5 I/min air this corresponded to a calculated NO delivery per pulse of252 nmoles/pulse which is very close to the predicted 43 nL×6 molarconcentration which equals 258 nmoles of sodium nitrite delivered.

Turning lastly to FIG. 12, there is a schematic view of a NO deliverysystem for use wherein the system has the capability of setting the NOconcentration to be administrated to a patient. As can be seen in FIG.12, there is, again, a pump 92 that draws in room air through a filter94 and pumps that air through the reaction chamber 96 with an optionalmembrane separation tube 98 located upstream of the reaction chamber 96.Conduit 100 delivers the NO-containing gas from the reaction chamber 96where it can be administered to the patient 102. There is an NO sensor104 to determine the concentration of NO in the stream of gas deliveredto the patient 102. As with the FIG. 8 system, a ventilator 106 breathesthe patient via an inspiratory limb 108 by means of an endotracheal tubeor face mask 110 while the exhaled gases from the patient are returnedto the ventilator 106 via an expiratory limb 112.

There is also a liquid dispense control 114 that controls the reactionoccurring within the reaction chamber 96 so that the amount of NOgenerated in the NO reaction chamber 96 is controlled and a pump control116 to control the pump 92. With this embodiment, there is also a flowsensor 118 that is located in the inspiratory limb 108 to measure theflow of the breathing air that is being provided by the ventilator 106to the patient 102 through that inspiratory limb 108.

In this embodiment, therefore, an input device 120 is provided so thatthe user can enter the desired concentration of NO to be administered tothe patient 102. Since the flow to the patient 102 is known from theflow sensor 118, the liquid dispense control 114 can control the NObeing generated in the NO reaction chamber to combine with that knownflow to deliver to NO concentration set by the user by the input device120.

Those skilled in the art will readily recognize numerous adaptations andmodifications which can be made to the NO generation system and methodof generating NO of the present invention which will result in animproved method and system for generating and directly introducing NOinto the airway of a patient, yet all of which will fall within thescope and spirit of the present invention as defined in the followingclaims. Accordingly, the invention is to be limited only by thefollowing claims and their equivalents.

What is claimed is:
 1. A method of controlled delivery of nitric oxide(NO) gas to the lung of a human patient in need thereof by inhalationcomprising: delivering aqueous droplets comprising dissolved nitritesalt compound via pulses from a first liquid dispenser to a location ona rotatable reaction surface at a first position in a reaction chamberin fluid communication with the lung by inhalation of the human patient;rotating the rotatable reaction surface to a second position; deliveringdroplets comprising a liquid reductant via pulses from a second liquiddispenser to substantially the same location on the rotatable reactionsurface in the reaction chamber as the aqueous droplets comprisingdissolved nitrite salt compound; generating NO gas by reacting thedissolved nitrite salt with the reductant in the reaction chamber; anddelivering an amount of the generated NO to the lung of the humanpatient; wherein the reductant comprises ascorbic acid and maleic acidat a 1:1 molar ratio.
 2. The method of controlled delivery of nitricoxide (NO) to the lung of a human patient in need thereof by inhalationaccording to claim 1, wherein generating NO comprises continuousreaction of the nitrite salt and the reductant.
 3. The method ofcontrolled delivery of nitric oxide (NO) to the lung of a human patientin need thereof by inhalation according to claim 1, wherein the NO isdelivered at a concentration in a range of 5 ppm to 80 ppm.
 4. Themethod of controlled delivery of nitric oxide (NO) to the lung of ahuman patient in need thereof by inhalation according to claim 1,wherein the nitrite salt compound is sodium nitrite.
 5. The method ofcontrolled delivery of nitric oxide (NO) to the lung of a human patientin need thereof by inhalation according to claim 1, wherein the dropletsare delivered at a rate based upon an alveolar volume of the patient anda concentration of NO to be inhaled by the patient.
 6. The method ofcontrolled delivery of nitric oxide (NO) to the lung of a human patientin need thereof by inhalation according to claim 1, further comprisingthe step of controlling the amount of NO delivered to the lung of thepatient by controlling the frequency at which the aqueous nitrite saltcompound droplets are contacted with the liquid reductant.
 7. A devicefor controlled intermittent or continuous delivery of nitric oxide (NO)gas to the lung of a human patient in need thereof by inhalation, thedevice comprising: a reaction chamber comprising a rotatable reactionsurface in fluid communication with the lung by inhalation with thehuman patient; a first controllable liquid dispensing system adapted tospray aqueous droplets comprising dissolved nitrite salt compound to alocation in the reaction chamber at a pulsed rate into contact with aliquid reductant; a second controllable liquid dispensing system adaptedto spray at a pulsed rate the liquid reductant at substantially the samelocation on the rotatable reaction surface in the reaction chamber asthe aqueous droplets comprising dissolved nitrite salt compound; and anoutlet for discharging NO gas from the reaction chamber for delivery tothe patient; wherein delivery of NO gas to the lung is controlled bycontrolling the frequency at which the aqueous nitrite salt compounddroplets are contacted with the liquid reductant, and wherein thereductant comprises ascorbic acid and maleic acid at a 1:1 molar ratio.8. The device for controlled intermittent or continuous delivery ofnitric oxide (NO) to the lung of a human patient in need thereof byinhalation according to claim 7, wherein the first controllable liquiddispensing system is comprised of at least one micropump.
 9. The devicefor controlled intermittent or continuous delivery of nitric oxide (NO)to the lung of a human patient in need thereof by inhalation accordingto claim 8, wherein the second controllable liquid dispensing system iscomprised of at least one micropump.
 10. The device for controlledintermittent or continuous delivery of nitric oxide (NO) to the lung ofa human patient in need thereof by inhalation according to claim 7,wherein the droplets have a volume in the range of 10 picoliters to 100picoliters.
 11. The device for controlled intermittent or continuousdelivery of nitric oxide (NO) to the lung of a human patient in needthereof by inhalation according to claim 7, wherein the nitrite saltcompound is sodium nitrite.
 12. The device for controlled intermittentor continuous delivery of nitric oxide (NO) to the lung of a humanpatient in need thereof by inhalation according to claim 7, furthercomprising a ventilator adapted to provide inspiratory gas to thepatient through the device for controlled delivery of NO.
 13. The devicefor controlled intermittent or continuous delivery of nitric oxide (NO)to the lung of a human patient in need thereof by inhalation accordingto claim 7, further comprising an input device adapted to set thedesired concentration of NO to be delivered to the patient, and a flowsensor adapted to determine the flow of gas provided by the ventilator,wherein the amount of NO delivered to the patient is based on thedesired concentration entered into the input device.
 14. A device forcontrolled intermittent or continuous delivery of nitric oxide (NO) gasto the lung of a human patient in need thereof by inhalation, the devicecomprising: a reaction chamber comprising a rotatable reaction surfacein fluid communication with the lung by inhalation with the patient; afirst controllable liquid dispensing system adapted to spray aqueousdroplets comprising dissolved nitrite salt compound in the range of 10picoliters to 100 picoliters at a pulsed rate into contact with a liquidreductant; a second controllable liquid dispensing system adapted tospray at a pulsed rate the liquid reductant at substantially the samelocation on the rotatable reaction surface in the reaction chamber asthe aqueous droplets comprising dissolved nitrite salt compound; anoutlet for discharging NO gas from the reaction chamber for delivery tothe patient; a ventilator in fluid communication with the outlet andadapted to provide inspiratory gas to the patient through the device forcontrolled delivery of NO gas; wherein delivery of NO gas to the lung iscontrolled by controlling the frequency at which the aqueous nitritesalt compound droplets are contacted with the liquid reductant; whereinthe nitrite salt compound is sodium nitrite and the liquid reductant isascorbic acid and maleic acid; and wherein the ascorbic acid and maleicacid are at a 1:1 molar ratio.
 15. The device for controlledintermittent or continuous delivery of nitric oxide (NO) to the lung ofa human patient in need thereof by inhalation according to claim 14,wherein the first controllable liquid dispensing system is comprised ofat least one micropump.
 16. The device for controlled intermittent orcontinuous delivery of nitric oxide (NO) to the lung of a human patientin need thereof by inhalation according to claim 14, wherein the secondcontrollable liquid dispensing system is comprised of at least onemicropump.